Phospholipids are amipathic compounds that tend to self-associate in aqueous systems to form micelles with a hydrophobic interior and hydrophilic exterior. Two types of structures can be formed by phospholipids. One type is vesicles in which a phospholipid bilayer encloses an aqueous internal space. Since the phospholipid bi-layer acts as a barrier between the aqueous internal space and the outer aqueous environment, various water-soluble compounds can be sequestered in the internal aqueous space. As a result, this particular structure has been used as a drug-delivery system (see G. Gregoriadis, New England J. Med. 295 704 (1976) and G. Gregoriadis, New England J. Med. 295 765 (1976)).
Another type of system that phospholipids can form is microemulsions in which a highly water-insoluble substance, such as cholesterols, cholesterol esters and derivatives, or triglycerides, forms an inner core surrounded by an outer monolayer of phospholipid (see L. Shorr et al., Biophys. J. 17 81a (1977)). Since the interior of these structures is hydrophobic, compounds which are nonpolar can be sequestered in the interior core of these microemulsion structures.
While both of such structures offer potentially new methods of drug delivery, much of this potential is modulated by the fact that both drug-delivery systems only have activity if directly injected into the blood-stream. Usually oral administration is not possible, since the phospholipids used would be hydrolyzed in the stomach, and hence any associated drug would be released, in whole or in part, in the stomach, and would be hydrolyzed by itself or at least exhibit a decrease in the maximal effectiveness of the drug. On the other hand, if the phospholipids could be altered in such a manner to resist hydrolysis, then oral administration of such drug-delivery systems is possible, as the delivery system would be able to pass through the stomach intact and then be absorbed by the gut.
The major enzymes responsible for the hydrolysis of phospholipids in mammals are phospholipase A and phospholipase C.
Phospholipase A.sub.2, which hydrolyzes the acyl chains of phospholipids, is maximally active at the transition temperature when the phospholipids are melting into a liquid crystalline state (see J.A.F. Op Den Kamp et al., Biochem. Biophys. Acta 406 169 (1975)). At temperatures in which the phospholipid is in the gel state, the enzyme is relatively inactive. Furthermore, if the acyl linkages to the glycerol backbone of the phospolipids are replaced by ether linkages, then the phospholipid is totally inactive. Thus, phospholipase A.sub.2 hydrolysis can be prevented rather easily.
Phospholipase C hydrolyzes the polar moiety of the phospholipid. Therefore, the physical state of the acyl chains has little bearing on the hydrolysis of the polar-head group. Thus, it is desirable to minimize or eliminate phospholipase C hydrolysis of phospholipids, and to permit the use of phospholipids in drug-delivery systems.
One technique of employing phospholipids, such as synthetic lecithins, to prepare controlled-release pharmaceutical compositions, is described in U.S. Pat. No. 4,016,100, issued Apr. 5, 1977, hereby incorporated by reference. This method comprises the steps of: dispersing a phospholipid uniformly in water to give an aqueous phospholipid dispersion having lipid spherules; adding a medicament to the aqueous phospholipid dispersion to form a medicament dispersion; freezing said medicament dispersion, thereby entrapping the medicament in the lipid spherules; and then thawing the frozen dispersion to give an aqueous suspension of the medicament entrapped in said lipid spherules. In such techniques, a wide variety of pharmaceutical compounds may be used, including bronchodilators, vitamins, medicants, hormones, antibiotics, including water-insoluble and water-soluble compounds. However, the use of the phospholipids described is not wholly satisfactory, due to the rapid hydrolysis of such phospholipids on oral administration of the encapsulated compounds.